Clinically useful antagonists exist for estrogens, androgens, and mineralocorticoids. Antagonists for the glucocorticoids or the progestins with potential clinical usefulness have been discovered only recently. The objective of this project is to develop and study the molecular mechanisms of action and the human applications of the antagonists for both of these classes of steroids. Initially, we proved that glucocorticoid antagonists can be developed by modifications of the 11-position of the steroidal C ring of glucocorticoids. Then we tested a prototype glucocorticoid-progestin antagonist (RU 38486) developed recently by Roussel-UCLAF. This compound has strong affinities for the human glucocorticoid and progestin receptor and is devoid of agonist effects. Given to nonhuman primates or man it causes prolonged elevations of plasma ACTH, cortisol and arginine vasopressin, all changes preventable by previous administration of glucocorticoid (dexamethasone). Thus, antiglucocorticoids could be used for challenging the hypothalamic-pituitary-adrenal axis when clinical testing is required in patients with disorders of this axis. We also used RU 38486 to treat a patient with severe hypercortisolism due to ectopic ACTH secretion. The therapy caused remission of the clinical manifestations of Cushing's syndrome in this patient. We are planning to enlarge the therapy series. We are currently studying the molecular mechanisms of action, and the effects and the pharmacokinetic properties of this drug in nonhuman primates and man. Four new, potentially better analogs of RU 38486, will be provided by Schering Co. for both basic studies and potential clinical applications.